Composition containing ergotamine, caffeine and hydantoin derivatives for cephalalgia



United States Patent ()ffice 3,15%,552 Fatented Dec. 8, 1364 3,160,562CUMPOSITIQN CONTAINlNG ERGGTAMKNE,

C ENE AND ANTGlN DERIVA- TWlld FOR QEFHALALGZA Aurelio Cerletti,Bottmingen, Basel-Land, and Albert Fanchamps, Basel, Switzerland,assignors to Sandoz Ltd. (also known as dander A.G.), Basel, SwitzerlandNo Drawing. Filed June 25, 1963, Ser. N 2%,300 (Ilaims priority,application France dune 27, 1962 2 Claims. (Cl. 16765) The presentinvention relates to a pharmaceutical composition comprising a mixtureof active ingredients having unexpected properties.

The present invention provides a pharmaceutical composition containing,in addition to an inert, physiologically acceptable carrier, (i)dihydroergotamine or an acid addition salt thereof, (ii) cafieine and(iii) 5,5- diphenylhydantoin (i.e., phenytoin) or3-rnethyl-5-ethyl-5-phenylhydantoin (i.e., rnephenytoin). The preferredcomposition of the present invention is the one containing phenytoin.This pharmaceutical composition is especially suitable for treatingheadache patients, e.g., for prophylactic treatment of migraine.

It should be noted that the hydantoin may be present in the form of analkali metal salt and this is also within the scope of the presentinvention.

Preferably, the quantities of (i), (ii) and (iii) are 00005-0002 g.,0.020.l g. and ODS-0.2 g. respectively per unit of dosage In general,these ranges are to be understood in such a way that the actual amountsof the three constituents present are chosen at corresponding points inthe ranges, e.g., all three constituents should be present in themaximum amount and not a maximum of one with a minimum of the other two.

The compositions of the invention are preferably in the form of soliddosage units, i.e., are formed as discrete units, each such unitcontaining a single dose of each of the ingredients (i), (ii) and (iii).Especially preferred discrete units are tablets, capsules lozenges andpills; however, they may likewise be in the form of suppositories, thecarrier being a suppository base.

Cafi'eine has a mitigating effect on cephalalgia crises, but this isusually insuflicient when used alone; hence it has been proposed to useit in combination with an analgesic or ergotamine. Ergotamine or anergotamine/catfeine mixture, also termed Caiergot (registered trademark) have an inhibitory or curative effect on cephalalgia, especiallyon the onset of migraine; although they constitute an excellent specifictreatment for this, some patients sufiering from headaches are notamenable to this treatment, e.g., because of undesirable side etlects.

Dihydroergotamine has a preventive effect on certain forms of headaches;when regularly administered during prolonged treatment it prevents theonset of cephalalgia crises, but all patients do not respond equallyfavourably to this treatment. For example, this treatment is inefiective with persons, suite-ring from headaches, whose electroencephalogram(EEG) shows dysrhythmia.

It has now been discovered, surprisingly, that the composition of theinvention has a preventive efiect especially in the case of trigeminalneuralgia and headaches which are not amenable to other pharmaceuticalsand that it is especially suitable for prophylactic treatment ofcephalalgia, especially migraine. Headaches which show a dysrhythmia orother anomalies of the EEG have been found to respond favourably topropyhlactic treatment with the composition of the invention. Itstherapeutic indication, however, does not limit it to these headachesand headaches which are not accompanied by dysrhythmia of the EEG alsorespond favourably to treatment with the composition of the presentinvention.

The composition of the present invention has been tested successfully inprophylactic treatment of the following complaints:

(1) Vasomotor headaches and Hortons syndrome,

(2) Headaches with dysrhythmia of the EEG,

(3) Migraine,

(4) Headaches of various origin which do not respond favourably to otherpharmaceuticals,

(5 Trigeminal neuralgia.

The effectiveness of the composition of the present invention inminimizing or preventing the types of headache described above could notbe predicted from the properties of its constituents. The essentialfeature of the invention is the combination of one of the two hydantoinsmentioned above with dihydroergotamine and caffeine, but it is stressedthat even the combination of (i) dihydroergotamine and (ii) cafieine isalso novel. Neither of the said two hydantoins has analgesic or vascularproperties; their pharmacological action essentially consists in raisingthe convulsive threshold, as is shown in pharmacological tests withanimals and in clinical tests with humans. The only therapeuticindication hitherto known for these two hydantoin is the treatment ofcertain forms of epilepsy; their use in the manner indicated herein forthe preventive treatment of headaches is an entirely new use which couldnot have been predicted from their pharmacological properties. A furtherunexpected efiect of the composition of the present invention is itspreventive effect in cases or" neuralgic crises of trigeminal neuralgia.

The specific pharmaceutical compositions shown below were used forclinical tests. These specific compositions are given solely by way ofexamples and the composition of the present invention is not limited tothe weight ratios quoted below.

Drages A Drages B Substance Weight, Percent Weight, Percent gram gramDihydro-ergotamine methane sulphouate 0. 0010 0. 17 0. 0010 0. 17Anhydrous cafieine 0. 050 8. 33 0. 050 8. 33 5, 5- liphenylhydantoin 0.10 16. 67 3-methyl-Sethyl-Sphenylhydantoin 0. 10 16. 67

Drages A and B Weight, gram Percent Gelatine 0. 010 1. 67 Talc O. 0110l. 83 Stealic acid 0. 0120 2. 0 Maize starch 0. 040 6. 67 Lactosc 0.126021. 0 Drage pastet t0. 250 41. 66

t The 0.250 g. of drage paste consisted of:

Gum arable, 0. 8 g. Saccharose, 0.152 g. Talc, 0.090 g.

The dihydroergotamine methane sulphonate is mixed with about onetwentieth part of the total lactose; then the other two pharmaceuticallyactive substances and the rest of the lactose are added. Granulation isthen effected with an alcoholic solution of about one third of thestearic acid and an aqueous solution of the gelatine. The rest of thestearic acid is'then added to the dried granulate, together with thetalc and the maize starch and the mixture pressed into pellets which aremade into drages in manner known per se, so that 100 g. of drage mass isconverted into about 167 drages of 0.60 g. each.

In Table I below, clinical trial results with drages A above are shown;the initial treatment when it was successful was continued for 2-4weeks, whereafter the initial dosage (2 to 3 drages per day, 4-6 dragesin especially resistant cases) was progressively reduced in appropriatestages and finally discontinued, depending on the reaction to thetreatment of each individual patient.

TABLE I Therapeutic Effect Number Indication of cases treated Very goodGeodto None (no (complete mediocre preventive prevention) efieet)Vasoinotor headaches 94 41 37 1S Hortons syndrome. 1 1 Headaches withdysrhythmia of the E EG. 24 10 S 6 Migraine 25 G 9 10 Reealcitrantheadaches .9 5 0 4 Neuralgia of the trigeminal 2 1 1 Side effects wereobserved only rarely and then usually only mild ones.

Clinical tests carried out with drages B gavesimilar therapeuticresults.

A comparative pharmacological investigation of acute toxicity caused bythat composition of the present invention which contains phenytoin, andthe toxicity of each of its three active constituents was thenundertaken.

The 50% lethal dosages (DL 50) are indicated in Table 2 below.

From the foregoing it will be seen that the beneficial therapeuticeffect of the composition of the present invention is due to asynergistic efiect possessed by the combination of thedihydroergotarnine, cafieine and one of the two specified hydantoins; asopposed to previously known cephalalgia treatments, the composition ofthe present invention has been found to have a prophylactic effect.

Whatis claimed is:

1. A pharmaceutical composition consisting of (i) a m mber of the groupconsisting of dihydroergotamine and pharmaceutically acceptable acidaddition salts thereof, (ii) caffeine, (iii) a member of the groupconsisting of 5,5-diphenylhydantoin and3-methyl-S-ethyl-S-phenylhydantoin, and an inert, physiologicallyacceptable carrier wherein the quantities of (i), (ii) and (iii) are0.0005-0.002 g., 0.020.1 g. and ODS-0.2 g. respectively, per unit ofdosage.

2. A pharmaceutical composition according to claim 1, consisting ofdihydroergotarnine methane-sulphonate, caffeine,5,5-dipl1enyl-hydantoin, and an inert, physiologically acceptablecarrier.

No references cited.

1. A PHARMACEUTICAL COMPOSITION CONSISTING OF (I) A MEMBER OF THE GROUPCONSISTING OF DIHYDROERGOTAMINE AND PHARMACEUTICALLY ACCEPTABLE ACIDADDITION SALTS THEREOF, (II) CAFFEINE, (III) A MEMBER OF THE GROUPCONSISTING OF 5,5-DIPHENYLHYDANTOIN AND3-METHYL-5-ETHYL-5-PHENYLHYDANTOIN, AND AN INERT, PHYSIOLOGICALLYACCEPTABLE CARRIER WHEREIN THE QUANTITIES OF (I), (II) AND (III) ARE0.0005-0.002 G., 0.02-0.1 G. AND 0.05-0.2 A RESPECTIVELY, PER UNIT OFDOSAGE.